Long-term histological effects of high-dose prednisolone administration on the mitral valve in normal Beagle dogs.

Background: In recent years, left ventricular hypertrophy and cardiac dysfunction have been reported in human and canine patients with hypercortisolism and in dogs treated experimentally with high-dose prednisolone. However, to our knowledge, there have been no reports on the effects of hyperglucocorticism (HGC) on the mitral valve (MV). Aim: This study aimed to compare the MV in dogs treated with high-dose prednisolone with that in healthy dogs to investigate the effects of HGC on the MV. Methods: We investigated the effects of HGC on the MV by comparing samples obtained from high-dose glucocorticoid (GC)-treated (P) and healthy (C) dogs. The P group included healthy Beagle dogs (n = 6) treated with prednisolone (2 mg/kg, bid, po) for 84 days and the C group included healthy Beagle dogs (n = 6) euthanized for unrelated reasons. The anterior and posterior mitral leaflets (AML and PML, respectively) from both groups were harvested and stained with hematoxylin-eosin, Alcian blue, and Masson trichome. Additionally, adiponectin (ADN) and GC receptor immunohistochemistry were performed. Histological evaluation was performed in the atrialis, spongiosa, fibrosa, and all layers of the proximal, middle, and distal regions of the AML and PML. Results: The proportion of the spongiosa layer thickness to the total thickness was higher in the P than in the C group (proximal and middle AML). However, the proportion of the fibrosa layer thickness to the total thickness was lower in the P than in the C group (middle PML). Areas of acidic sulfated mucosubstance deposition were smaller in the fibrosa layer and all layers (middle AML), while those of collagen deposition were smaller in the spongiosa and total layers (proximal and middle AML), in the P than in the C group. Additionally, ADN expression in the spongiosa layer was higher in the P than in the C group (middle AML). Conclusion: These findings suggest that long-term administration of synthetic GCs induces histological changes in the MV. These changes may lead to MV dysfunction in dogs with HGC.

Mechanism of long-term high-dose prednisolone administration producing myocardial fibrosis in beagle dogs.

Background: We previously reported that myocardial fibrosis may be one of the causes of left ventricular hypertrophy and cardiac dysfunction in dogs with hyperglucocorticism (HGC). The detailed mechanism by which myocardial fibrosis of the left ventricle occurs in dogs with HGC remains unclear. Aim: Th is study investigated the mechanism by which HGC causes fibrosis of the left ventricle. Methods: The impa cts of HGC on the heart by comparing samples obtained from high-dose glucocorticoid (GC)-treated (P) and untreated (C) dogs. The P group included healthy Beagle dogs (n = 6) treated with prednisolone (2 mg/kg, bid, po) for 84 days, and the C group included healthy Beagle dogs (n = 6) euthanized for unrelated reasons. In three of the P group dogs, serum was collected before the start of administration (Day 0) and on Day 84 to measure angiotensin II concentrations and oxidative stress markers (8-hydroxy-2'-deoxyguanosine (8OHdG), NADPH oxidase, and superoxide levels). Samples of the left ventricular free wall (LVFW), right ventricular free wall (RVFW), interventricular septum (IVS), and aortic root were harvested from both groups (n = 6 for each group). Using these tissue samples, angiotensin II type 1 receptor (AT1R), 8OHdG, and transforming growth factor ß1 (TGFß1) immunohistochemical stains were performed. Results: The blood N ADPH oxidase concentration was significantly higher (p = 0.027) in the P group 84 days after initiation of the medication compared to that before prednisolone treatment. By contrast, there was no significant difference in serum angiotensin II (p = 0.450), 8OHdG (p = 0.068), and superoxide (p = 0.057) concentrations. The positive staining rates of AT1R, 8OHdG, and TGFß1 in the heart (LVFW, RVFW, IVS, and aortic root) were significantly higher in the P group than those in the C group. Conclusion: Angiotensin II and oxidative stress in HGC may cause left ventricular fibrosis in dogs.

Adrenocorticotropic hormone-producing pituitary adenoma with pituitary apoplexy treated by surgical decompression: a case report.

BACKGROUND: Pituitary-dependent hypercortisolism (PDH) is one of the most common endocrine disorders in veterinary medicine. However, there are few reports on pituitary tumor apoplexy (PTA) in dogs and no reports on its surgical intervention in veterinary medicine. Accordingly, the appropriate treatment is unknown. Herein, a case of PDH and PTA in a dog treated surgically is described. CASE PRESENTATION: A mongrel female dog (spayed; age, 8 years and 8 months; weight, 6.1 kg) with persistently elevated alkaline phosphatase underwent adrenocorticotropic hormone (ACTH) stimulation testing (post-stimulation cortisol: 20.5 µg/dL), abdominal ultrasonography (adrenal gland thickness: left, 5.7 mm; right, 8.1 mm), and brain magnetic resonance imaging (MRI) (pituitary-to-brain ratio [PBR], 0.61) at the referral hospital, resulting in a diagnosis of PDH (day 0). On day 9, the dog visited XXXX for the preparation of pituitary surgery to treat PDH. However, on days 10-15, the dog developed a loss of energy and appetite, bloody diarrhea, vomiting, and a decreased level of consciousness. However, on day 16, the dog's condition recovered. A preoperative MRI scan performed on day 52 (the day of surgery) showed apoplexy in the dorsal pituitary region (PBR, 0.68). Based on the PTA findings, the risks of surgery were described to the owner, and approval was obtained. At the time of trans-sphenoidal surgery, a partial pituitary resection was performed with preservation of the PTA area due to adhesions between the PTA area of the right side of the pituitary and surrounding tissues. The resected pituitary tissue was diagnosed as an ACTH-producing adenoma, with necrotic and hemorrhagic findings. As of day 290, endogenous ACTH and cortisol levels did not exceed the reference range. CONCLUSIONS: The acute signs that occurred on days 10-15 were most likely caused by PTA. Therefore, when signs similar to those detected in acute hypoadrenocorticism are observed in dogs with PDH, it is necessary to include PTA as a differential diagnosis. Trans-sphenoidal surgery may be effective in PDH-affected dogs that develop PTA, but careful attention should be paid to tissue adhesions secondary to hemorrhage that may occur after PTA.

Three Cases of Transtracheal Catheter Oxygenation for Postoperative Dyspnoea with Pituitary-Dependent Hyperadrenocorticism in Dogs Treated by Surgery.

Transsphenoidal surgery (TSS) is a curative treatment for pituitary-dependent hyperadrenocorticism, and its use in dogs has recently increased. One of the most serious postoperative complications of TSS is dyspnoea. We report three cases where transtracheal catheter oxygen therapy prevented death from respiratory distress secondary to enlarged soft palate after TSS.

Effects of long-term and high-dose administration of glucocorticoids on the cranial cruciate ligament in healthy beagle dogs.

This study aimed to determine the effects of long-term and high-dose administration of glucocorticoids (GCs) on the histological and mechanical properties of the cranial cruciate ligament (CrCL) in healthy beagle dogs. A synthetic corticosteroid at 2 mg/kg every 12 h was administered for 84 days in nine dogs (18 CrCLs) (GC group). Twenty CrCLs from 12 healthy male beagles were used as the normal control (control group). CrCLs were histologically examined (n = 12 in the GC group and n = 14 in the control group) using hematoxylin-eosin, Alcian-Blue, Elastica-Eosin stains, and immunohistological staining of type 1 collagen and elastin. An additional 12 CrCLs were mechanically tested (n = 6 in the GC and n = 6 in the control groups) to determine failure pattern, maximum tensile strength, maximum stress, elastic modulus, and stress and strain at the transition point. The histological examination revealed a significant increase in interfascicular area and fibrillar disorientation at the tibial attachment in both groups. The ratios of mucopolysaccharide-positive area and positive areas of elastic fibers were significantly higher in the control group than in the GC group. The biomechanical examination demonstrated significantly lower stress at the transition point in the GC group than in the control group. The present study results indicate that high-dose corticosteroids may affect metabolism, such as mucopolysaccharides and elastic fibers production, although the effect on type 1 collagen production is small. These changes of the extracellular matrix had a small effect on the strength of the ligament. This study suggested that the ligamentous changes associated with GC are different from the degeneration observed in spontaneous canine CrCL disease.

Utility of a corticotropin-releasing hormone test to differentiate pituitary-dependent hyperadrenocorticism from cortisol-producing adrenal tumors in dogs.

BACKGROUND: Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin-releasing hormone test (CRHT) to differentiate between pituitary-dependent hyperadrenocorticism (PDH) and cortisol-producing adrenal tumors (CPATs), both causative of HAC. OBJECTIVES: To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. ANIMALS: Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). METHODS: This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary-to-brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). RESULTS: For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10-17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42-33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. CONCLUSIONS AND CLINICAL IMPORTANCE: CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs.

Long-term administration of prednisolone: Effects on the myocardial tissue of healthy beagle dogs.

This study aimed to assess the structural and functional effects of long-term hyperglucocorticoidemia on canine myocardium and compare these parameters with histopathological changes. Twelve healthy male beagle dogs were enrolled and assigned to the high-dose prednisolone (P; n=6) and control (C; n=6) groups. The P group was treated with 2 mg/kg of prednisolone BID for 84 days. Clinical parameters were measured using echocardiography and non-invasive systolic blood pressure (SBP) measured before the initiation of synthetic corticosteroids and at 7, 28, 56, and 84 days after the start of medication. For histological evaluation, cardiovascular tissue was harvested from dogs in groups P (at the end of the medication period) and C (scheduled to be euthanized for unrelated reasons). In the P group, clinical changes including thickening of the left ventricular free wall (LVFW) and interventricular septum (IVS), decreased left ventricular (LV) diastolic function, and increased SBP were observed after the start of medication. During histological evaluation, fibrosis was observed in the LVFW and IVS in the P group. Furthermore, decreased glucocorticoid receptor (GCR) levels were observed in the LVFW, right ventricular free wall (RVFW), and IVS and increased mineralocorticoid receptor (MCR) levels were observed in the LVFW and RVFW in the P group compared with those in the C group. In conclusion, fibrosis may cause LV structural and functional abnormalities in dogs with hyperadrenocorticism. Furthermore, GCR downregulation and upregulated MCR might influence the myocardial fibrosis.

Collection of homozygous mutant mouse embryonic stem cells arising from autodiploidization during haploid gene trap mutagenesis.

Haploid mouse embryonic stem cells (ESCs), in which a single hit mutation is sufficient to produce loss-of-function phenotypes, have provided a powerful tool for forward genetic screening. This strategy, however, can be hampered by undesired autodiploidization of haploid ESCs. To overcome this obstacle, we designed a new methodology that facilitates enrichment of homozygous mutant ESC clones arising from autodiploidization during haploid gene trap mutagenesis. Haploid mouse ESCs were purified by fluorescence-activated cell sorting to maintain their haploid property and then transfected with the Tol2 transposon-based biallelically polyA-trapping (BPATrap) vector that carries an invertible G418 plus puromycin double selection cassette. G418 plus puromycin double selection enriched biallelic mutant clones that had undergone autodiploidization following a single vector insertion into the haploid genome. Using this method, we successfully generated 222 homozygous mutant ESCs from 2208 clones by excluding heterozygous ESCs and ESCs with multiple vector insertions. This relatively low efficiency of generating homozygous mutant ESCs was partially overcome by cell sorting of haploid ESCs after Tol2 BPATrap transfection. These results demonstrate the feasibility of our approach to provide an efficient platform for mutagenesis of ESCs and functional analysis of the mammalian genome.

Serum albumin level accurately reflects antioxidant potentials in idiopathic nephrotic syndrome.

BACKGROUND: Recent observation revealed that serum albumin plays an important role in the host defense mechanism as it is one of the important antioxidants. This study was conducted to investigate whether hypoalbuminemia contributes to a decreased biological antioxidant potentials (BAP) in idiopathic nephrotic syndrome (INS). METHODS: Fifty three heparinised blood samples were obtained from 8 patients with INS (median 13.5 years). Eighteen samples from 6 patients with Henoch-Schönlein purpura (HSP median 7 years) were served as control. Intravenous human albumin preparation was also applied for comparison. Measurement of BAP in blood and human albumin preparation was determined by a newly developed devise called FRAS4(®). Comparison among groups and relationships between BAP and albumin concentrations or c-reactive protein (CRP) were studied by Kruskal-Wallis test and Spearman rank correlation test, respectively. RESULTS: Serum levels of BAP was significantly lower in patients with nephrotic relapse than those in patients with nephrotic remission or HSP. BAP correlated well with serum albumin levels. Positive relationship was also found between concentration of albumin in human preparation and BAP. Weakly positive CRP sera disclosed both hypoalbuminemia and low BAP. CONCLUSION: Our results suggest that decreased antioxidant potentials caused by hypoalbuminemia in INS may contribute to an aberrant immunity.

Immunoglobulin preparations affect hyponatremia in Kawasaki disease.

Hyponatremia frequently occurs in Kawasaki disease (KD). The aim of this study was to investigate the effect of Na content of the intravenous immunoglobulin (IVIG) preparation on serum Na levels in KD. Seventy-eight subjects, of whom 27 had hyponatremia, were split up into two groups: group A receiving IVIG preparations containing high Na (0.9%) and group B receiving IVIG preparations containing trace Na. While the data before IVIG therapy revealed no significant differences in the median serum Na between the groups, an administration of IVIG preparations increased the serum levels of Na in group A (P < 0.01) but not in group B (P > 0.05). Furthermore, the median serum Na level was significantly higher in group A than that in group B (139.0 vs 137.0 mEq/L, respectively, P < 0.01). No significant difference was found in the prevalence of coronary artery lesions between the groups. In conclusion, we should keep it in mind that the IVIG products without Na have an adverse affect on hyponatremia in KD though their efficacy seems to be equivalent to those containing high Na.

A family with X-linked benign familial hematuria.

Gene mutations in COL4A5 located on Xq22 are believed to cause X-linked Alport syndrome, whereas mutations in COL4A3 and COL4A4 located on chromosome 2 are associated with autosomal inherited Alport syndrome or benign familial hematuria. A family with benign familial hematuria caused by COL4A5 mutation, implying X-linked transmission, is reported here for the first time. This result suggests that COL4A5 should be added to the list of causative genes for benign familial hematuria, although the mechanism(s) by which the same mutation leads to the distinct phenotypes, i.e. X-linked Alport syndrome or benign familial hematuria, remains unknown.

The genes influencing adiponectin levels also influence risk factors for metabolic syndrome and type 2 diabetes.

Results from previous studies suggest that adiponectin levels are associated with risk factors for cardiovascular disease and type 2 diabetes mellitus; however, the genetic and/or environmental components of this relationship have not been characterized. The aims of this study were (1) to assess the presence of pleiotropy between adiponectin levels and risk factors for cardiovascular disease and (2) to study the association of circulating levels of adiponectin with risk factors for cardiovascular disease in the absence and presence of obesity in Mexican American adults from the San Antonio Family Heart Study. Body composition and circulating levels of adiponectin, leptin, and lipid subfractions and measurements of glucose metabolism were measured in 898 subjects. The mean and standard error of the circulating levels of adiponectin was 8.7 +/- 3.2 microg/ml. Bivariate quantitative analyses between adiponectin levels and phenotypes related to cardiovascular disease and type 2 diabetes mellitus were conducted using the variance decomposition approach implemented in SOLAR. A second analysis in unrelated subjects compared these risk factors between sex- and age-matched lean and obese subjects with high and low adiponectin levels. We found significant evidence of pleiotropy (i.e., shared genetic effects) between plasma levels of adiponectin and well-established risk factors for cardiovascular disease and type 2 diabetes mellitus. Individuals with low adiponectin levels per body weight had more adverse risk profiles. These findings offer new insights into the genetic connection between increasing adiposity and risk for cardiovascular disease and type 2 diabetes mellitus, and they suggest that adiponectin may be an important risk factor for the development of these conditions.

Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.

Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.

Analysis of gene expression in poplar trees (Populus deltoides x nigra, DN34) exposed to the toxic explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).

Poplar plants (Populus deltoides x nigra, DN34) growing under hydroponic conditions were exposed to 50 mg L(-1) of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) for 24 h. The expression of genes potentially involved in the metabolism of toxic explosives was analyzed by reverse-transcriptase (RT) real-time PCR. Genes under study were selected by reference to corresponding genes that were previously shown to be upregulated in the model plant Arabidopsis thaliana by exposure to 2,4,6-trinitrotoluene (TNT) (Ekman et al., 2003. Plant Physiol., 133, 1397-1406). The target genes investigated include several genes encoding for enzymes known to be involved in the detoxification of xenobiotic pollutants, such as glutathione S-transferases (GSTs), cytochrome P-450s (CYPs), NADPH-dependent reductases, and peroxidases. Starting from A. thaliana TNT-inducible genes, corresponding Populus sequences were retrieved from the JGI Poplar Genome Project database and were used to design gene-specific primers. 18S ribosomal DNA (rDNA) was used as an internal standard and recorded gene expression levels were normalized by reference to nonexposed plants. In three separate experiments, five genes were found to be significantly amplified in leaf tissues by exposure to RDX, including GST (9.7 fold), CYP (1.6 fold), reductases (1.6-1.7 fold), and peroxidase (1.7 fold). In root tissues, only a single GST gene was found to be significantly amplified by exposure to RDX (2.0 fold). These results show, for the first time, that the exposure of poplar plants to RDX results in the induction of several genes that are potentially involved in explosive detoxification.

High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels.

The association of mRNA expression levels of leptin receptors (long isoform: Lep-R(L) and short isoform: Lep-R(S)) in breast cancer tissue with patient prognosis was studied with special reference to the serum leptin level or the leptin mRNA level in tumor tissue. Lep-R(L), Lep-R(S) and leptin mRNA levels in breast cancer tissue (n = 91) were determined with a real-time PCR assay, and serum leptin levels in breast cancer patients (n = 67) with an enzyme-linked immunosorbent assay. Neither Lep-R(L) nor Lep-R(S) mRNA levels in tumor tissue were significantly associated with patient prognosis, but both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly (p < 0.01) associated with a poor prognosis. Multivariate analysis showed that a high level of both Lep-R (L) and Lep-R (S) mRNA in tumor tissue was a significant risk factor, independent of other risk factors. The subset analysis demonstrated that both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly associated with a poor prognosis for the subset of patients with high serum leptin or high intratumoral leptin mRNA levels but not in the subset of patients with low serum leptin or low intratumoral leptin mRNA levels. The association between both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors and a poor prognosis in the presence of high serum leptin or high intratumoral leptin mRNA levels seems to suggest that the leptin and Lep-R(L)/Lep-R(S) pathways are implicated in the growth stimulation of breast tumors. The well-established finding that obesity serves as a risk factor for relapse in breast cancer patients may thus be partially explained by the high serum leptin level seen in obese women.

Common Polymorphisms in the Adiponectin Gene ACDC Are Not Associated With Diabetes in Pima Indians.

Adiponectin is an abundant adipose tissue-derived protein with important metabolic effects. Plasma adiponectin levels are decreased in obese individuals, and low adiponectin levels predict insulin resistance and type 2 diabetes. Two variants in the adiponectin gene ACDC have been previously associated with plasma adiponectin levels, obesity, insulin resistance, and type 2 diabetes. To determine the role of genetic variation in ACDC in susceptibility to obesity and type 2 diabetes in Pima Indians, we screened the promoter, exons, and exon-intron boundaries of the gene to identify allelic variants. We identified 17 informative polymorphisms that comprised four common (minor allele frequency >15%) linkage disequilibrium clusters consisting of 1-4 variants each. We genotyped one representative polymorphism from each cluster in 1,338 individuals and assessed genotypic association with type 2 diabetes, BMI, serum lipid levels, serum adiponectin levels, and measures of insulin sensitivity and secretion. None of the ACDC variants were associated with type 2 diabetes, BMI, or measures of insulin sensitivity or secretion. One variant, single nucleotide polymorphism (SNP)-12823, was associated with serum adiponectin levels (P = 0.002), but this association explained only 2% of the variance of serum adiponectin levels. Our findings suggest that these common ACDC polymorphisms do not play a major role in susceptibility to obesity or type 2 diabetes in this population.

Adiponectin concentrations are influenced by renal function and diabetes duration in Pima Indians with type 2 diabetes.

Adiponectin is produced exclusively by adipocytes, and its serum concentration is inversely associated with adiposity. This study examines the relationship among diabetes, renal function, and serum adiponectin in Pima Indians. Serum adiponectin was measured in 1069 people in whom glycemia and renal function had been measured. Serum adiponectin, adjusted for age, sex, and body mass index, was lowest in those with impaired glucose regulation or diabetes of less than 10 yr duration and highest in those with normal glucose tolerance or diabetes of duration of at least 10 yr. Both urinary albumin to creatinine ratio (ACR) and serum creatinine were positively correlated with adiponectin (Spearman's r = 0.43; P < 0.0001, and r = 0.37; P < 0.0001, respectively) in diabetic subjects. After stratification by albuminuria (normoalbuminuria ACR < 30 mg/g, microalbuminuria ACR = 30-299 mg/g, and macroalbuminuria ACR >or= 300 mg/g), the highest adiponectin concentration was in the macroalbuminuria group (geometric mean = 9.6 microg/ml) and the lowest was in the normoalbuminuric group (geometric mean = 5.6 microg/ml). After adjustment for age, sex, body mass index, and diabetes duration, the serum adiponectin concentration in the macroalbuminuria group was significantly higher than in both other groups (P < 0.0001). Serum adiponectin is lowest in the presence of impaired glucose regulation and early diabetes. In the presence of diabetes, serum adiponectin is positively associated with abnormal renal function and diabetes duration.

Genome-wide linkage analysis of serum adiponectin in the Pima Indian population.

Adiponectin is a circulating protein secreted by adipocytes and is thought to have insulin-sensitizing effects. We present genetic analysis of adiponectin levels in 517 Pima Indians without diabetes (from 162 families, 750 sib-pairs). Adiponectin concentrations were heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences in this population. In genome-wide linkage analyses, suggestive linkage (logarithm of odds [LOD] = 3.0) of adiponectin adjusted for age and sex was found on chromosome 9p at 18 cM. Linkage was also present after inclusion of adiponectin concentrations of siblings with type 2 diabetes not treated pharmacologically (total siblings 582, 182 families, 860 sib-pairs: LOD = 3.5). Tentative evidence of linkage was also found on chromosomes 2 (LOD = 1.7 at 89 cM), 3 (LOD = 1.9 at 124 cM), and 10 (LOD = 1.7 at 70 cM), offering some support to findings of a previous genome-wide scan of adiponectin. Our data suggest that quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in the Pima population.